Use of neridronic acid or of its salt for the treatment of osteoarthrosis

ABSTRACT

The use of neridronic acid or a salt thereof in the treatment of osteoarthritis is described. In particular, neridronic acid or a salt thereof has been shown to be able to reduce significantly the symptoms of osteoarthritis, such as pain and physical and mobility disabilities, as well as subchondral bone marrow lesions underlying the onset of such symptoms.

FIELD OF THE INVENTION

The present invention relates to the use of neridronic acid or a saltthereof in the treatment of osteoarthritis. In particular, neridronicacid or a salt thereof has been shown to be able to reduce significantlythe symptoms of osteoarthritis, such as pain and physical disabilities,as well as subchondral bone marrow lesions underlying the onset of suchsymptoms.

BACKGROUND ART

Osteoarthritis (OA) is, along with hypertension, the disease with thehighest prevalence in the world over fifty years old population and isthe most common cause of chronic disability. Given the epidemiologicalimportance of said disease, to date there are no recognized effectivetherapeutic strategies capable of modifying the disease course,slowing/stopping the anatomical progression of joint damage.

The therapeutic objectives which can be currently pursued are thereforeonly aimed at reducing painful symptoms and functional deficitsassociated therewith.

Despite the several guidelines and consensus documents published so far(Nelson A E et al. Sem Arthritis Rheum, 2014), the optimal strategies inthe clinical management of pain symptoms in patients suffering fromarthritis are not yet unanimous. This is due to different confusingaspects: firstly, due to the typical features of arthritic pain, usuallyfloating over time with possible intense painful recrudescence lastingweeks/months capable of permanently affecting the degree of disabilityof the patient; secondly, due to the large number of proposedtherapeutic approaches, whether based on physical (non-pharmacological),pharmacological (intra-articular and systemic) or surgical therapies.

At present, the non-pharmacological approach, understood as joint savingstrategy (functional limitation and reduction of body weight on bearingjoints) and which may involve the use of specific tools (braces,splints, Canadian sticks) and the kinesitherapic approach (maintainingthe muscle tone/trophism and joint mobility through specificrehabilitative exercises) turns out to be the most unanimous therapeuticstrategy, despite the clear limitations of a modest impact on painsymptoms. Similarly, other instrumental physical therapies such as thelocal application of radiation or ultrasonographic waves does not havean unanimous utility and above all, is poorly effective at the level ofjoint sites frequently affected by arthritis, such as the large jointsof the lower limb (hip and knee).

The surgical approach is solely aimed at a preventive (correction ofanatomic defects which cause an altered load) or radical strategy, suchas prosthetic joint replacement, where possible, of joints severelyanatomically damaged.

The pharmacological strategy is the strategy usually and widely used inthe management of arthritis pain. In these terms, the need for a chronicor in any case prolonged therapy, the old age of the patient and thusthe frequent presence of other diseases and relevant treatmentsrepresent the obstacles which the clinician must systematically dealwith. The most conservative approach refers to the use of minoranalgesics such as paracetamol, which usually shows a fair risk-benefitprofile when used at the dosages usually prescribed for treating chronicpain symptoms, i.e. minor pain experienced daily by the patient, whileit is only modestly effective in treating middle/high intensityarthritic pain.

Conversely, major analgesics (opioids), i.e. with a stronger analgesiceffect, are difficult to use due to the high rate of adverse eventsobserved in elderly patients.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is affected bythe tolerance limits related to the need for continued use in elderlypatients, i.e. the risk of gastrointestinal side effects for traditionalNSAIDs and of cardiovascular adverse events as regards next generationNSAIDs (e.g. Coxib).

Similarly, to date the intra-articular administration of drugs does nothave a widely unanimous consensus, both with regard to the use ofcortisone derivatives, due to their chondrolesive potential whenadministered at high dosages or high frequency, and with regard to theuse of hyaluronate, which does not seem to be able to provide asubstantial benefit in the treatment of painful symptoms, particularlyin the treatment of acute painful poussees.

Finally, a possible therapeutic role of bisphosphonates (briefly “BPs”)was also investigated.

A number of studies have been published on the subject, which actuallycover only retrospective assessments of possible effects onosteoarthritis, exclusively based on data recorded for certain BPsadministered in the treatment of postmenopausal osteoporosis. BPs are aclass of drugs widely and specifically used in the treatment ofpostmenopausal osteoporosis and other skeletal disorders characterizedby an altered bone metabolism.

Among the various prospective studies carried out in order to evaluatesaid possible therapeutic role of some BPs on the anatomical progressionof osteoarthritis, in particular the studies on aminobisphosphonaterisedronate conducted by Bingham C O (Arthritis Rheum 54, 2006,3494-3507) and Spector T D et al. (Arthritis Research Ther 2005, 7:R625-33) are significant, but they did not provide positive results inthis regard. In fact, according to the authors of said studies, it wasnot possible to find any difference, in terms of efficacy of treatmentin pain symptoms, between the group of patients treated with the BPs andthe group of patients treated with placebo, at any of the dosages tested(5, 15, 35 and 50 mg).

In particular, Spector T D et al. point out that the preliminaryclinical data obtained on the effect of risedronate one year aftertreatment were not then replicated and confirmed in the subsequent studyextended to two years of treatment.

Therefore, even the possibility of a therapeutic use of BPs, and inparticular of aminobisphosphonates, in the treatment of OA, andparticularly of pain symptoms and physical disabilities of patientssuffering from OA, does not appear to be a viable strategy.

Therefore, it is an object of the present invention to find an effectiveremedy capable of acting on the conditions of an arthritic patient inorder to improve the symptoms thereof, such as pain and disability.

SUMMARY OF THE INVENTION

Said object has been achieved by using neridronic acid or a salt thereofin the treatment of osteoarthritis as stated in claim 1.

In particular, neridronic acid or a salt thereof has been shown to beable to reduce significantly the symptoms of osteoarthritis, such aspain and disabilities, as well as subchondral bone marrow lesionsunderlying the onset of such symptoms.

In another aspect, the present invention relates to a pharmaceuticalcomposition to be administered intravenously, comprising said neridronicacid or a salt thereof for use in the treatment of osteoarthritis, andto pharmaceutically acceptable vehicles for intravenous administration.

In a further aspect, the present invention relates to a vial or bottlefor intravenous administration comprising neridronic acid or a saltthereof for use in the treatment of osteoarthritis.

In an even further aspect, the present invention relates to apharmaceutical composition to be administered intramuscularly,comprising said neridronic acid or a salt thereof for use in thetreatment of osteoarthritis, and to pharmaceutically acceptable vehiclesfor intramuscular administration.

In another aspect, the present invention relates to a vial or bottle forintramuscular administration comprising neridronic acid or a saltthereof for use in the treatment of osteoarthritis.

BRIEF DESCRIPTION OF THE DRAWINGS

The characteristics and the advantages of the present invention willbecome apparent from the following detailed description, from theworking examples provided for illustrative purposes, and from theannexed Figures wherein:

FIG. 1 shows the apportionment of patients recruited for the study ofExample 1;

FIG. 2 shows the trend of the VAS parameter during the 60 days followingthe beginning of treatment of patients according to the study of Example1.

DETAILED DESCRIPTION OF THE INVENTION

The invention thus relates to neridronic acid or a salt thereof for usein the treatment of osteoarthritis (briefly, “OA”).

In particular, as it will be also apparent from the examples givenhereinafter, neridronic acid or a salt thereof has been shown to be ableto reduce significantly the symptoms of osteoarthritis, such as pain andphysical disabilities, as well as the size of subchondral bone marrowlesions.

Therefore, it was surprisingly found that neridronic acid or a saltthereof has proved to be able to successfully treat osteoarthritis byrelieving mild, moderate or severe symptoms ascribable thereto, inparticular moderate or severe symptoms.

Neridronic acid or a salt thereof has been shown to be able tosuccessfully treat mild, moderate or severe pain symptoms in patientssuffering from osteoarthritis, particularly OA of the hip, knee or hand,especially OA of the knee.

Moreover, it was surprisingly found that neridronic acid or a saltthereof has shown to be able to successfully treat osteoarthritis byrelieving joint stiffness and improving mobility and physicalfunctionality.

In particular, neridronic acid or a salt thereof has been shown to beable to successfully treat joint stiffness, by improving mobility andphysical functionality in patients suffering from OA of the hip, knee orhand, especially OA of the knee.

As it will be clear from the examples given hereinafter, neridronic acidor a salt thereof has been shown to reduce significantly pain intensityin patients with OA, as well as joint stiffness, and advantageouslyimprove mobility and physical functionality even after more than 50 dayssince the end of treatment.

Neridronic acid or a salt thereof has further proved to be able to treatpain in patients with OA during acute painful poussee.

In fact, it was surprisingly found that neridronic acid or a saltthereof has proved to be able to reduce the sizes and extents of bonemarrow lesions associated with arthritis pain symptoms.

The examples given hereinafter show that neridronic acid or a saltthereof can successfully improve the pattern of subchondral bone marrowlesions detectable by nuclear magnetic resonance (NMR).

For the purposes of the present invention, the term “neridronic acid ora salt thereof” is understood to include all polymorphic forms, bothamorphous and crystalline, as well as co-crystalline and anhydrous,hydrated and solvate forms.

Preferably, said neridronic acid is in the form of a salt. Saidneridronic acid salt is alkaline or alkaline-earthy neridronate salt,such as sodium neridronate or potassium neridronate, quaternary ammoniumsalt of neridronate or a mixture thereof.

In a preferred embodiment, said neridronic acid salt is sodiumneridronate.

Neridronic acid or a salt thereof is to be preferably administered at adosage of 10-500 mg.

Said neridronic acid or a salt thereof can be administered orally,intramuscularly, intravenously, intraarticularly, transdermally,subcutaneously or topically.

Preferably, said neridronic acid or a salt thereof is to be administeredintravenously.

Neridronic acid or a salt thereof is to be administered intravenously,preferably at a dosage of 25-400 mg. More preferably, said neridronicacid or a salt thereof is to be administered at least 2 times, with atleast 1 day between an administration and a subsequent one.

For the purposes of the present invention, the term “day” means a periodof 24±2 hours.

Therefore, said neridronic acid or a salt thereof can be used accordingto dosing regimens comprising daily administrations, alternate-dayadministrations, or administrations every at least two or three days andbeyond.

Preferably, said neridronic acid or a salt thereof is to be administeredintravenously at a dosage of 50-200 mg, at least 2 times over a periodof 5-15 days, with at least 1 day between an administration and asubsequent one.

In preferred embodiments, said neridronic acid or a salt thereof is tobe administered intravenously at a dosage of 50-200 mg, at least 3 timesover a period of 5-15 days, with at least 2 days between anadministration and a subsequent one.

In other preferred embodiments, said neridronic acid or a salt thereofis to be administered intravenously at a dosage of 70-150 mg, 4 timesover a period of 8-12 days, with 2 days between an administration and asubsequent one.

Alternatively, said neridronic acid or a salt thereof is to beadministered intravenously at a dosage of 70-150 mg, 4 times over aperiod of 8-12 days, with 3 days between an administration and asubsequent one.

In the most preferred embodiments, said neridronic acid or a saltthereof is to be administered intravenously at a dosage of 90-110 mg, 4times over a period of 10 days, with 3 days between an administrationand a subsequent one.

In an even more preferred embodiment, said neridronic acid is in theform of sodium salt (sodium neridronate) to be administeredintravenously at a dosage of 90-110 mg, 4 times over a period of 10days, with 3 days between an administration and a subsequent one.

In a further even more preferred embodiment, said neridronic acid in theform of sodium salt (sodium neridronate) is to be administeredintravenously at a dosage of 100 mg of neridronic acid, 4 times over aperiod of 10 days, with 3 days between an administration and asubsequent one. In this way, the intravenous administration can becarried out on days 1, 4, 7 and 10 of treatment.

As can be seen from the example below, the results of the randomizedcontrolled study demonstrated that sodium neridronate can be usedeffectively for treating patients with OA. In particular, the results ofthis study demonstrated that sodium neridronate can be used effectivelyto reduce the mild, moderate or severe pain symptoms, and even morespecifically moderate or severe symptoms, in patients with OA.

Specifically, sodium neridronate can be used effectively to reduce painsymptoms in patients with OA having basal VAS (greater than or equal to)30 mm.

Specifically, a course of sodium neridronate administered intravenouslycan be used effectively to treat patients with OA, and in particular toreduce mild, moderate or severe pain symptoms in patients with OA.

In particular, the study demonstrated that a course of sodiumneridronate administered intravenously reduces the pain intensity inpatients with symptomatic OA of the knee.

The study also demonstrated that the size and extent of BMLs decreasedsignificantly in patients treated with sodium neridronate compared topatients treated with placebo only.

That is, sodium neridronate can be used effectively for treatingpatients with OA undergoing acute painful poussees, thus reducing theextent of bone marrow lesions.

In addition, the study demonstrated that the treatment of patients withOA with sodium neridronate allowed an effective and long lastingsymptomatic treatment, and thereby pain control, even after more than 50days since the end of treatment.

The advantageous results achieved with the present invention in thetreatment of osteoarthritis, especially in the treatment of mild,moderate or severe pain symptoms in patients with OA are thereforeevident, especially considering that these results were unexpected inview of the prior art related to BPs, particularly toaminobisphosphonates, such as risedronate.

In preferred embodiments, said neridronic acid or a salt thereof is inthe form of an aqueous solution of neridronic acid or a salt thereof.Said aqueous solution is preferably isotonic or hypotonic, even morepreferably hypotonic.

Said neridronic acid or a salt thereof is further preferably present asa unit dose comprising 1-10 ml of aqueous solution in a vial or bottle,preferably a glass vial or bottle. Preferably, said unit dose comprises2, 5 or 8 ml of an aqueous solution in a vial or bottle.

Preferably, said unit dose comprises 70-150 mg of neridronic acid or asalt thereof.

In a particularly preferred embodiment, said unit dose comprises 100 mgof neridronic acid or comprises a salt thereof in an amount equivalentto 100 mg of neridronic acid.

Therefore, according to a further aspect thereof, the present inventionalso relates to a vial or bottle for intravenous administrationcomprising neridronic acid or a salt thereof for use in the treatment ofosteoarthritis.

Preferably, said vial or bottle comprises a unit dose of 70-150 mg ofneridronic acid or a salt thereof.

More preferably, said vial or bottle comprises 100 mg of neridronic acidor comprises a salt thereof in an amount equivalent to 100 mg ofneridronic acid.

Advantageously, said vial or bottle is in a ready-to-use form.

In another aspect, the present invention relates to a pharmaceuticalcomposition comprising said neridronic acid or a salt thereof for use inthe treatment of osteoarthritis, and pharmaceutically acceptablevehicles for the oral, intramuscular, intravenous, intra-articular,transdermal, sub-cutaneous or topical administration.

Specifically, said pharmaceutical composition comprising said neridronicacid or a salt thereof, and pharmaceutically acceptable vehicles for theoral, intramuscular, intravenous, intra-articular, transdermal,sub-cutaneous or topical administration, is for use in the treatment ofosteoarthritis of the hip, knee or hand, preferably it is for use in thetreatment of osteoarthritis of the knee.

Preferably, said pharmaceutical composition is to be administeredintravenously and comprises said neridronic acid or a salt thereof foruse in the treatment of osteoarthritis, and pharmaceutically acceptablevehicles for intravenous administration.

Pharmaceutically acceptable vehicles suitable for intravenousadministration are for example, pH adjusters, isotonicity adjusters,stabilizers, chelating agents, preservatives and antioxidants.

Preferred pH adjusters are citric acid, sodium citrate, sodium acetate,boric acid, sodium borate, sodium bicarbonate, phosphoric acid and saltsthereof, even more preferably citric acid and sodium citrate (citratebuffer) and sodium bicarbonate.

Among isotonicity adjusters, sodium chloride is preferred.

Among stabilizers, mannitol, dextran or mixtures thereof are preferred.

Among chelating agents, EDTA or a salt thereof, such as sodium EDTA, ispreferred.

Among antioxidants, sodium metabisulphite, potassium metabisulphite,sodium bisulphite, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid and sodium ascorbate are preferred.

Among preservatives, benzyl alcohol, methyl paraben and propyl parabenare preferred.

In a preferred embodiment, said pharmaceutical composition to beadministered intravenously comprises sodium neridronate for use in thetreatment of osteoarthritis, citrate buffer and sodium chloride.

In another preferred embodiment, said pharmaceutical composition to beadministered intravenously comprises sodium neridronate for use in thetreatment of osteoarthritis, sodium bicarbonate and sodium chloride.

In other preferred embodiments, in said pharmaceutical composition to beadministered intravenously, said neridronic acid or a salt thereof isthe only active ingredient present for use in the treatment ofosteoarthritis.

Alternatively, said pharmaceutical composition to be administeredintravenously consists of said neridronic acid or a salt thereof for usein the treatment of osteoarthritis, and pharmaceutically acceptablevehicles for intravenous administration.

Preferably, the pharmaceutical composition is in the form of an aqueoussolution. Said aqueous solution is preferably isotonic or hypotonic,even more preferably hypotonic.

Said pharmaceutical composition is further preferably present as a unitdose comprising 1-10 ml of aqueous solution in a vial or bottle,preferably a glass vial or bottle. Preferably, said unit dose comprises2, 5 or 8 ml of an aqueous solution in a vial or bottle.

Preferably, said unit dose comprises 70-150 mg of neridronic acid or asalt thereof.

In a particularly preferred embodiment, said unit dose comprises 100 mgof neridronic acid or comprises a salt thereof in an amount equivalentto 100 mg of neridronic acid.

According to a further aspect, the present invention therefore alsorelates to a vial or bottle for intravenous administration comprisingneridronic acid or a salt thereof for use in the treatment ofosteoarthritis.

Preferably, said vial or bottle comprises a unit dose of 70-150 mg ofneridronic acid or a salt thereof.

More preferably, said vial or bottle comprises 100 mg of neridronic acidor comprises a salt thereof in an amount equivalent to 100 mg ofneridronic acid.

Advantageously, said vial or bottle is in a ready-to-use form.

Preferably, said neridronic acid or a salt thereof is sodium neridronatefor use in the treatment of osteoarthritis.

More preferably, said vial or bottle is for the intravenousadministration of sodium neridronate for use in the treatment ofosteoarthritis.

Alternatively, said neridronic acid or a salt thereof is to beadministered intramuscularly.

Neridronic acid or a salt thereof is to be administered intramuscularlypreferably at a dosage of 10-100 mg.

Preferably, said neridronic acid or a salt thereof is to be administeredintramuscularly at a dosage of 15-50 mg, more preferably at a dosage of25 mg of neridronic acid or at an equivalent dosage of a salt thereof,preferably sodium neridronate.

In the particularly preferred embodiments, said neridronic acid or asalt thereof is sodium neridronate to be administered intramuscularly ata dosage of 15-50 mg, 1 to 20 times over a period of 1-30 days.

In the most preferred embodiments, said neridronic acid or a saltthereof is sodium neridronate to be administered intramuscularly at adosage of 25 mg of neridronic acid, 1 to 16 times over a period of 1-16days.

In an even further aspect, the present invention relates to apharmaceutical composition to be administered intramuscularly andcomprises said neridronic acid or a salt thereof for use in thetreatment of osteoarthritis, and pharmaceutically acceptable vehiclesfor intramuscular administration.

Pharmaceutically acceptable vehicles suitable for intramuscularadministration are for example, pH adjusters, isotonicity adjusters,stabilizers, chelating agents, preservatives and antioxidants.

Preferred pH adjusters are citric acid, sodium citrate, sodium acetate,boric acid, sodium borate, sodium bicarbonate, phosphoric acid and saltsthereof, even more preferably citric acid and sodium citrate (citratebuffer) and sodium bicarbonate.

Among the isotonicity adjusters, sodium chloride is preferred.

Among the stabilizers, mannitol, dextran or mixtures thereof arepreferred.

Among the chelating agents, EDTA or a salt thereof, such as sodium EDTA,is preferred.

Among the antioxidants, sodium metabisulphite, potassium metabisulphite,sodium bisulphite, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid and sodium ascorbate are preferred.

Among preservatives, benzyl alcohol, methyl paraben and propyl parabenare preferred.

In a preferred embodiment, said pharmaceutical composition to beadministered intramuscularly comprises sodium neridronate for use in thetreatment of osteoarthritis, citrate buffer and sodium chloride.

In another preferred embodiment, said pharmaceutical composition to beadministered intramuscularly comprises sodium neridronate for use in thetreatment of osteoarthritis, sodium bicarbonate and sodium chloride.

In other preferred embodiments, in said pharmaceutical composition to beadministered intramuscularly, said neridronic acid or a salt thereof isthe only active ingredient present for use in the treatment ofosteoarthritis.

Alternatively, said pharmaceutical composition to be administeredintramuscularly consists of said neridronic acid or a salt thereof foruse in the treatment of osteoarthritis, and pharmaceutically acceptablevehicles for intramuscular administration.

Preferably, the pharmaceutical composition is in the form of an aqueoussolution of neridronic acid or a salt thereof. Said aqueous solution ispreferably isotonic or hypotonic, even more preferably hypotonic.

Said pharmaceutical composition is further preferably present as a unitdose comprising 1-10 ml of aqueous solution in a vial or bottle,preferably a glass vial or bottle. Preferably, said unit dose comprises2, 5 or 8 ml of an aqueous solution in a vial or bottle.

Preferably, said unit dose comprises 10-100 mg of neridronic acid or asalt thereof.

In a particularly preferred embodiment, said unit dose comprises 25 mgof neridronic acid or comprises a salt thereof in an amount equivalentto 25 mg of neridronic acid.

According to a further aspect thereof, the present invention thereforealso relates to a vial or bottle for intramuscular administrationcomprising neridronic acid or a salt thereof for use in the treatment ofosteoarthritis.

Advantageously, said vial or bottle is in a ready-to-use form.

Preferably, said neridronic acid or a salt thereof is sodium neridronatefor use in the treatment of osteoarthritis.

More preferably, said vial or bottle is for the intramuscularadministration of sodium neridronate for use in the treatment ofosteoarthritis.

Alternatively, said neridronic acid or a salt thereof is to beadministered orally or sublingually.

In yet a further aspect, the present invention relates to apharmaceutical composition to be administered orally or sublingually andcomprises said neridronic acid or a salt thereof for use in thetreatment of osteoarthritis, and pharmaceutically acceptable vehiclesfor oral or sublingual administration.

Suitable pharmaceutically acceptable vehicles for oral or sublingualadministration for example are natural starch, partially hydrolyzedstarch, lactose, glucose, sucrose, mannitol, sorbitol, cellulose andderivatives thereof, microcrystalline cellulose and derivatives thereof,calcium phosphate, calcium carbonate, calcium sulfate, magnesiumstearate, maltodextrin, gelatin, gum tragacanth, arabic gum, xanthangum, talc, silica, colloidal silica, precipitated silica, magnesiumsilicates, aluminum silicates, sodium lauryl sulfate, magnesium laurylsulfate, methacrylate copolymers, and mixtures thereof.

Said composition for oral or sublingual administration can be in theform of powder, capsule, tablet, mini-tablet, micro-tablet, granule,microgranule, pellet, multi-particulate or micronized particles.Alternatively, it may be in liquid form, i.e. in solution, dispersion orsuspension with suitable pharmaceutically acceptable solvents.

All pharmaceutical compositions described above can be prepared by usingmethods known in the art according to the route of administration.

A method is also described for the treatment of osteoarthritis,comprising the steps of:

i) providing neridronic acid or a salt thereof,

ii) administering a therapeutically effective amount of said neridronicacid or a salt thereof to a patient suffering from osteoarthritis.

In step i), said neridronic acid or a salt thereof can be in the form ofan aqueous solution of neridronic acid or a salt thereof, as describedabove.

Preferably, said neridronic acid or a salt thereof is provided as a unitdose comprising 1-10 ml of aqueous solution in a vial or bottle.

All the above-described advantageous and preferred aspects for use ofneridronic acid or a salt thereof are to be understood as similarlyadvantageous and preferred.

In particular, said method allows the pain symptoms of osteoarthritis tobe relieved in a patient suffering from osteoarthritis.

Preferably, in step ii), the administration of a therapeuticallyeffective amount of neridronic acid or a salt thereof to a patientsuffering from osteoarthritis relieves mild, moderate or severe symptomsascribable to osteoarthritis, in particular moderate or severe symptoms.

In particular, said administration relieves mild, moderate or severepain symptoms in patients suffering from osteoarthritis of the hip, kneeor hand, especially OA of the knee.

Specifically, said administration effectively reduces pain symptoms inpatients with OA having basal VAS (greater than or equal to) 30 mm.

Advantageously, said administration relieves joint stiffness andimproves the mobility and physical functionality of the patient.

The administration of neridronic acid or a salt thereof reduces painintensity in patients with OA, as well as joint stiffness andadvantageously improves mobility and physical functionality even aftermore than 50 days since the end of treatment.

More preferably, said administration relieves pain in patients with OAduring acute painful poussees.

In addition, the administration of neridronic acid or a salt thereofreduces the size and extent of bone marrow lesions associated with painsymptoms caused by arthritis, particularly in the case of OA of theknee.

A method is also described for the treatment of osteoarthritis,comprising the steps of:

i) providing a pharmaceutical composition comprising neridronic acid ora salt thereof as described above,

ii) administering a therapeutically effective amount of saidpharmaceutical composition to a patient suffering from osteoarthritis.

In step i), said pharmaceutical composition can be in the form of anaqueous solution of neridronic acid or a salt thereof, as describedabove.

Preferably, said pharmaceutical composition is provided as a unit dosecomprising 1-10 ml of aqueous solution of neridronic acid or a saltthereof in a vial or bottle.

All the above-described advantageous and preferred aspects for thepharmaceutical composition of neridronic acid or a salt thereof are tobe understood as similarly advantageous and preferred.

In particular, said method allows the pain symptoms of osteoarthritis tobe relieved in a patient suffering from osteoarthritis.

Preferably, the administration of a therapeutically effective amount ofa pharmaceutical composition of neridronic acid or a salt thereof to apatient suffering from osteoarthritis relieves mild, moderate or severesymptoms ascribable to osteoarthritis, in particular moderate or severesymptoms.

In particular, said administration relieves mild, moderate or severepain symptoms in patients suffering from osteoarthritis of the hip, kneeor hand, especially OA of the knee.

Specifically, said administration effectively reduces pain symptoms inpatients with OA having basal VAS (greater than or equal to) 30 mm.

Advantageously, said administration relieves joint stiffness andimproves the mobility and physical functionality of the patient.

The administration of a pharmaceutical composition of neridronic acid ora salt thereof reduces pain intensity in patients with OA, as well asjoint stiffness and advantageously improves mobility and physicalfunctionality, even after more than 50 days since the end of treatment.

More preferably, said administration relieves pain in patients with OAduring acute painful poussees.

In addition, the administration of a pharmaceutical composition ofneridronic acid or a salt thereof reduces the size and extent of bonemarrow lesions associated with pain symptoms caused by arthritis,particularly in the case of OA of the knee.

It is understood that all the aspects identified as preferred andadvantageous for the use of neridronic acid or a salt thereof are to bedeemed similarly preferred and advantageous also for the pharmaceuticalcompositions, vials, bottles, unit doses and their respective uses, aswell as for the methods of treating osteoarthritis.

All the combinations of preferred aspects of the use of neridronic acidor a salt thereof, the pharmaceutical composition, vial, bottle, unitdose and their respective uses, as well as of the methods of treatingosteoarthritis mentioned above are further understood as also described.

Below is a working example of the present invention provided forillustrative purposes.

EXAMPLE

The aim of this randomized, double-blind, placebo-controlled study wasto assess the efficacy of intravenous neridronate in controlling pain inpatients with acute painful knee osteoarthritis (OA).

Patients

From March 2013 to January 2014, 96 patients older than 50 years andwith a recent onset of knee pain were screened. These patients came fromthe orthopedic and rheumatologic outpatients services and the emergencydepartment of a tertiary care center devoted to bone and joint diseases.Sixty-eight patients were considered eligible to be recruited when theymet the following inclusion criteria:1) knee OA fulfilling the AmericanCollege of Rheumatology diagnostic criteria; 2) a radiographicKellgren-Lawrence grading score >2 in the tibiofemoral joint; 3) acontinuous knee pain by at least 2 weeks with an onset no longer thanthree months; 4) a pain intensity greater than 30 mm on a Huskisson'svisual analog scale ranging from 0 (no pain) to 100 mm (maximal pain);5) a knee MR scan showing large (>1 cm according to internationalcriteria) BMLs. Exclusion criteria were related to the presence ofinflammatory or metabolic diseases; the presence of routine laboratoryabnormalities (comprising calcemia, and glomerular filtration rate,which if altered are capable of increasing the risk of adverse events inpatients treated with BPs intravenously); prior treatment with BPs;evidence of significant joint effusion through MRI scan, morphologicalalterations at the subchondral bone joint profile suggestingosteonecrosis and/or evidence of bursitis or tendonitis; onset of painrelated to a specific traumatic event. At the time of recruitment, 58patients out of 68 (85.3%) were taking or had taken drugs to controlpain in the previous three months. The patients were asked not to takeany analgesics or nonsteroidal anti-inflammatory drugs (NSAIDs)throughout the study period. All patients gave written consent. Thestudy was approved by the Ethics Committee of the hospital where thestudy was carried out.

Study Design

After enrolment, patients were randomized to receive placebo or sodiumneridronate (Abiogen, Pisa, Italy) 100 mg/8 ml in vials with anidentical appearance in a 1:1 ratio.

Both sodium neridronate and placebo were diluted in 500 ml of salineisotonic solution and infused in the morning for over 2 hours. Thetreatment was administered every third day four times starting from day1 (first infusion) and ending on day 10 (fourth infusion).

Throughout the infusion course, serum calcium was assayed before eachinfusion. The values were adjusted for albumin value of 4.2 g/dL. After60 days (57-66) from the first infusion, the last clinical assessmentwas performed. Two months after the end of the study, patients wereinterviewed by telephone about a possible relapse of pain and thepossible resumption of analgesic drugs and/or NSAIDs. Knee magneticresonance imaging

High resolution, three-dimensional MRI of the target knee was obtainedfor each patient before the start of the treatment (1-7 days) and at theend of the study (day 58-69). All MR images were evaluated by a skilledmusculoskeletal radiologist who was blinded to the patient's treatment.All MR examinations were performed with a 1.5 T scanner (MagnetomEspree, Siemens) using a dedicated knee coil. Imaging was performed onsagittal, coronal and transverse planes, with a field of view (FOV) of18 cm and a matrix of acquisition of 256x256. The MR protocol included:spin echo (SE) T1-weighted sequences (repetition time TR 580 ms, echotime TE 12 ms, number of signal averages 2, thickness 3.0 mm,intersection gap 0.5 mm) on sagittal, coronal and transverse planes; SET2-weighted sequences (TR 4.000 ms, TE 30/100 ms, one signal acquired,thickness 3.0 mm, intersection gap 0.5 mm) on sagittal and transverseplanes; PD-weighted sequence with fat/suppression (TR 2800 ms, TE 40 ms,one signal acquired, thickness 3.0 mm, intersection gap 0.5 mm) oncoronal plane. Subchondral BMLs were identified as areas of increasesignal intensity on fat-suppressed T2-weighted images. Scores wereassigned using the Whole-Organ MRI score for knee OA (WORMS) for bonemarrow edema.

Specifically, BMLs were coded 0-3 in each of 10 subregions of the medialand lateral tibiofemoral compartments and in each of the four subregionsof the patellofemoral compartments. For each subregion, the extent ofthe lesion was assessed following the WORMS scale: 0=absence of edema;1=less than 25%; 2=25-50%; 3=>50%.

Measures

Primary outcome of the study was the assessment and comparison ofchanges in pain intensity between the sodium neridronate group and theplacebo group along the study.

Pain in the affected knee was measured by VAS (0-100) at day 1 (TO), atthe day of the last infusion (day 10; T1) and 50 days later (T2). Assecondary endpoints, the following clinical assessments were performed:the Western Ontario and MacMaster Universities Osteoarthritis Index(WOMAC) pain questionnaire; the McGill Pain Questionnaire and the36-Item Short Form Health Survey (SF-36) questionnaire to assess thepatient's functional status. All these instruments were administered atT0 and T2. As additional endpoint, changes in WORMS score before thetreatment and at T2 have been measured.

Results

Sixty-eight patients were recruited and randomized to treatment withsodium neridronate or placebo in two equal groups (34 patients). Atentry, the two groups were well balanced for demographic and clinicalcharacteristics (Table 1).

TABLE I Demographic, clinical and MRI characteristics of patients withpainful knee OA, prior to the beginning of treatment with neridronate orplacebo (baseline). Variables are expressed as average value ±corresponding standard deviations Neridronate Placebo N = 34 N = 34 P*Age 64.7 ± 11.8 67.0 ± 7.3  0.1 Gender (M/F): 19/15 18/16 0.6 BMI(Kg/m²) 25.7 ± 3.6  25.5 ± 3.9  0.7 Pain duration (weeks) 8.1 ± 2.2 6.8± 2.7 0.039 VAS score 59.0 ± 14.7 64.8 ± 16.9 0.1 WOMAC 232 ± 79  254 ±86  0.4 SF-36 physical component 36.6 ± 10.2 33.4 ± 6.7  0.4 SF-36mental component 56.1 ± 12.4 59.4 ± 13.2 0.1 McGill 14.3 ± 7.6  16.3 ±12.5 0.9 WORMS score 6.3 ± 3.0 7.7 ± 3.9 0.1 *Mann-Whitney U Test BMI:Body mass index; WOMAC: Western Ontario and MacMaster UniversitiesOsteoarthritis index; SF-36: 36-Item Short Form Health Survey; VAS:visual analog scale; McGill: McGill pain questionnaire; WORMS:Whole-Organ MRI score for knee OA.

Only the time elapsed since pain onset resulted slightly butsignificantly shorter in the placebo group. Fifty-six patients completedthe study. One of the patients in the sodium neridronate group withdrewthe consent for an adverse event (acute phase reaction) after the firstinfusion and one patient was excluded because of analgesic resumptionbefore the last clinical evaluation. Eight patients in the placebo groupwere excluded for the resumption of analgesic or NSAIDs treatment duringthe study (7 patients) and one patient refused to return to be evaluated50 days after the treatment. Two patients (one in the sodium neridronategroup and one in the placebo group) were excluded because theypresented—at the MRI performed at the end of the study—featuresevocative for an alteration of the joint bone profile evocative for apossible osteonecrosis (flattening/depression of the femoral condylesurface). The distribution of patients is shown in FIG. 1.

When VAS score was assessed at the day of the last infusion, both groupsshowed a significant decrease in comparison with basal values even if ahigher significant difference was observed in the sodium neridronategroup (FIG. 2). VAS score changed from 59.0±14.7 to 30.4±15.6 in thesodium neridronate group (p<0.001), while in the placebo group itdecreased from 64.8±16.9 to 55.4±17.4 (p=0.04). The comparison betweengroups at the day of the last infusion showed a significant greaterdecrease in the group of patients treated with sodium neridronate(p<0.001).

After the following 50 days, no further improvement in VAS score wasobserved in the placebo groups (FIG. 2) and the other clinical measuresshowed no change in the placebo before and after the treatment (Table2).

TABLE 2 Clinical characteristics of patients with painful knee OA,treated with neridronate or placebo, 50 days after the end of treatment.Variables are expressed as average value ± corresponding standarddeviations Neridronate Placebo N = 31 N = 25 P* VAS score  9.4 ±10.8^(†) 50.1 ± 16.9 0.001 WOMAC 58 ± 58^(†) 228 ± 162 0.001 SF-36physical component 51.1 ± 8.7^(†)  39.3 ± 19.1 0.01 SF-36 mentalcomponent 62.5 ± 11.1^(‡) 58.3 ± 13.8 0.2 McGill 3.7 ± 4.6^(†) 15.6 ±10.8 0.001 WORMS score 3.7 ± 4.2^(‡) 7.1 ± 3.6 0.002 *Mann-Whitney UTest P vs basal values: ^(†)= 0.001; ^(‡)= 0.01 (Wilcoxon signed ranktest) VAS: visual analog scale; WOMAC: Western Ontario and MacMasterUniversities Osteoarthritis index; SF-36: 36-Item Short Form HealthSurvey; McGill: McGill pain questionnaire; WORMS: Whole-Organ MRI scorefor knee OA.

At the last clinical evaluation, the sodium neridronate group showed afurther significant pain improvement with a VAS score which fell to9.4±10.8 (p<0.001 vs both T0 and T1 values). Also, other pain andfunctional rating indices showed significant decreases in comparisonboth with basal values and with placebo treated patients (Table 2).

The WORMS score revaluated at T2 showed a significant decrease in lesionsize only in the sodium neridronate group (from 6.3±3.0 to 3.7±4.2;p=0.01), while no significant change was observed in placebo treatedgroup (Table 2). Multivariate regression analyses on clinical variablesin patients treated with sodium neridronate demonstrated a correlationclose to significance between the VAS decrease observed on the day ofthe last infusion (T1) and the VAS decrease observed at the end of thestudy (β=0.452, p =0.01).When the patients were interviewed by phone twomonths after the last clinical evaluation, 18 patients out of 25 treatedwith placebo (i.e. as many as 72%) had resumed analgesic drugs orNSAIDs, while only 4 patients out of 31 treated with sodium neridronate(i.e. only 12.9%) had resumed the symptomatic therapy with analgesicdrugs or NSAIDs.

The results of this randomized controlled study therefore provideevidence that sodium neridronate can be effectively used for treatingpatients with OA.

In particular, the results of this study demonstrated that sodiumneridronate can be effectively used for reducing mild, moderate orsevere pain symptoms in patients with OA, and specifically moderate orsevere symptoms, in patients with OA.

Specifically, sodium neridronate can be effectively used for reducingpain symptoms in patients with OA having basal VAS (greater than orequal to) 30 mm.

Specifically, a course of sodium neridronate administered intravenouslycan be effectively used for treating patients with OA, and in particularfor reducing mild, moderate or severe pain symptoms, and specificallymoderate or severe symptoms, in patients with OA.

In particular, the study demonstrated that a course of sodiumneridronate administered intravenously reduces the pain intensity inpatients with symptomatic knee OA.

The study also demonstrated that the size and extent of BMLs decreasedsignificantly in patients treated with sodium neridronate compared topatients treated with a placebo.

That is, sodium neridronate can be effectively used for treatingpatients with OA undergoing acute painful poussees, reducing the extentof bone marrow lesions.

Finally, the study demonstrated that the treatment of patients with OAwith sodium neridronate allowed an effective and long lastingsymptomatic treatment, and thereby pain control, at least more than 50days since the end of treatment.

The advantageous results achieved by the present invention in thetreatment of osteoarthritis, especially in the treatment of mild,moderate or severe pain symptoms in patients with OA, are thereforeevident from the above description, especially considering that theseresults were unexpected in view of the prior art related to BPs,especially to aminobisphosphonates, such as risedronate.

1. A method of treating osteoarthritis comprising administering atherapeutically effective amount of neridronic acid or a salt thereof topatients in need thereofs.
 2. The method of claim 1, wherein thetreatment of osteoarthritis comprises alleviating the painsymptomathology of joint pain.
 3. The method of claim 1, wherein thetreatment of osteoarthritis comprises alleviating joint stiffness andimproving mobility and physical functionality.
 4. The method of claim 1,wherein the treatment of osteoarthritis comprises reducing the size andextent of bone marrow lesions.
 5. The method of claim 1, wherein saidsalt of neridronic acid is sodium neridronate.
 6. The method of claim 1,wherein said neridronic acid or a salt thereof is to be administered ata dosage of 10-500 mg.
 7. The method of claim 1, wherein said neridronicacid or a salt thereof is to be administered orally, intramuscularly,intravenously, intraarticularly, transdermally, subcutaneously ortopically.
 8. The method of claim 7, wherein said neridronic acid or asalt thereof is to be administered intravenously.
 9. The method of claim8, wherein said neridronic acid or a salt thereof is to be administeredintravenously at a dosage of 25-400 mg, at least 2 times, with at least1 day between an administration and a subsequent one. 10-14. (canceled)15. The method of claim 9, wherein said salt of neridronic acid issodium neridronate to be administered intravenously at a dosageequivalent to 100 mg of neridronic acid, 4 times over a period of 10days, with 3 days between an administration and a subsequent one. 16.The method of claim 15, wherein sodium neridronate is to be administeredintravenously on days 1, 4, 7 and
 10. 17. The method of claim 1comprising administering a therapeutically effective amount of apharmaceutical composition comprising neridronic acid or a salt thereof,and pharmaceutically acceptable vehicles for the oral, intramuscular,intravenous, intra-articular, transdermal, sub-cutaneous or topicaladministration.
 18. The method of claim 17, wherein said pharmaceuticalcomposition is administered intravenously, and comprises sodiumneridronate, sodium chloride, citric acid and sodium citrate or sodiumneridronate, sodium chloride and sodium bicarbonate .
 19. (canceled) 20.The method of claim 16 wherein said pharmaceutical composition ispresent as a unit dose comprising 1-10 ml of aqueous solution in a vialor bottle, said unit dose preferably comprising 70-150 mg of neridronicacid or a salt thereof.
 21. The method of claim 1 wherein saidtherapeutically effective amount of neridronic acid or salt thereof isadministered by a vial or bottle for intravenous administrationcomprising neridronic acid or a salt thereof.
 22. The method of claim 21wherein said vial or bottle comprises a unit dose of 70-150 mg ofneridronic acid or a salt thereof.
 23. The method of claim 22 whereinsaid vial or bottle comprises 100 mg of neridronic acid or a saltthereof in an amount equivalent to 100 mg of neridronic acid.
 24. Themethod of claim 21, wherein said salt of neridronic acid is sodiumneridronate.
 25. (canceled)
 26. The method of claim 7, wherein saidneridronic acid or a salt thereof is administered intramuscularly. 27.The method of claim 26, wherein said neridronic acid or a salt thereofis administered intramuscularly at a dosage of 10-100 mg.
 28. The methodof claim 27, wherein said salt of neridronic acid is sodium neridronateto be administered intramuscularly at a dosage equivalent to 25 mg ofneridronic acid.
 29. (canceled)